Loss of Epigenetic Modification Driven by the Foxp3 Transcription Factor Leads to Regulatory T Cell Insufficiency

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• 作者：Matthew  ; L. Bettinip>1p> ; Fan Panp>4p> ; Maria Bettinip>1p> ; David Finkelsteinp>2p> ; Jerold  ; E. Rehgp>3p> ; Stefan Floessp>5p> ; Bryan  ; D. Bellp>6p> ; Steven  ; F. Zieglerp>6p> ; Jochen Huehnp>5p> ; Drew  ; M. Pardollp>4p> ; Dario  ; A.A. Vignalip>1p>p> ; p>p>vignali.lab@stjude.orgp>
• 刊名：Immunity
• 出版年：2012
• 期刊代码：40_10747613
• 类别：imm
• 出版时间：25 May, 2012
• 卷：36
• 期：5
• 页码：717-730
• 文件大小：1306 K

摘要

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Summary

Regulatory T (Treg) cells, driven by the Foxp3 transcription factor, are responsible for limiting autoimmunity and chronic inflammation. We showed that a well-characterized Foxp3p>gfpp> reporter mouse, which expresses an N-terminal GFP-Foxp3 fusion protein, is a hypomorph that causes profoundly accelerated autoimmune diabetes on a NOD background. Although natural Treg cell development and in聽vitro function are not markedly altered in Foxp3p>gfpp> NOD and C57BL/6 mice, Treg cell function in inflammatory environments was perturbed and TGF-尾-induced Treg cell development was reduced. Foxp3p>gfpp> was unable to interact with the histone acetyltransferase Tip60, the histone deacetylase HDAC7, and the Ikaros family zinc finger 4, Eos, which led to reduced Foxp3 acetylation and enhanced K48-linked polyubiquitylation. Collectively this results in an altered transcriptional landscape and reduced Foxp3-mediated gene repression, notably at the hallmark IL-2 promoter. Loss of controlled Foxp3-driven epigenetic modification leads to Treg cell insufficiency that enables autoimmunity in susceptible environments.